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Unique treatment potential of cannabidiol for the prevention of relapse to drug use: preclinical proof of principle

Neuropsychopharmacologyvolume 43pages20362045 (2018) | Download Citation

Abstract

Cannabidiol (CBD), the major non-psychoactive constituent of Cannabis sativa, has received attention for therapeutic potential in treating neurologic and psychiatric disorders. Recently, CBD has also been explored for potential in treating drug addiction. Substance use disorders are chronically relapsing conditions and relapse risk persists for multiple reasons including craving induced by drug contexts, susceptibility to stress, elevated anxiety, and impaired impulse control. Here, we evaluated the “anti-relapse” potential of a transdermal CBD preparation in animal models of drug seeking, anxiety and impulsivity. Rats with alcohol or cocaine self-administration histories received transdermal CBD at 24 h intervals for 7 days and were tested for context and stress-induced reinstatement, as well as experimental anxiety on the elevated plus maze. Effects on impulsive behavior were established using a delay-discounting task following recovery from a 7-day dependence-inducing alcohol intoxication regimen. CBD attenuated context-induced and stress-induced drug seeking without tolerance, sedative effects, or interference with normal motivated behavior. Following treatment termination, reinstatement remained attenuated up to ≈5 months although plasma and brain CBD levels remained detectable only for 3 days. CBD also reduced experimental anxiety and prevented the development of high impulsivity in rats with an alcohol dependence history. The results provide proof of principle supporting potential of CBD in relapse prevention along two dimensions: beneficial actions across several vulnerability states and long-lasting effects with only brief treatment. The findings also inform the ongoing medical marijuana debate concerning medical benefits of non-psychoactive cannabinoids and their promise for development and use as therapeutics.

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Acknowledgements

This is publication number 29366 from the Scripps Research Institute. The CBD gel preparation was generously provided by Zynerba Pharmaceuticals, Inc, (Devon, PA) and AllTranz, Inc. (Lexington, KY). We thank the students Christine Chan, William Choy, Yunchen Ding, Li Huang, Tao Moua, Mark Sanderson-Cimino, and Angela Wong for assistance.

Author contributions

FW and ALS conceived the study. GGC, FW, and RMF designed the experiments. GGC and FW analyzed the data and wrote the manuscript. GGC and RMF conducted the behavioral tests. SLB developed and prepared the transdermal CBD gel formulation. TMK, DGS, and LHP performed tissue extraction and LC-MS assays of CBD brain levels. DCH performed the LC-MS assays of CBD plasma levels.

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Author notes

    • Gustavo Gonzalez-Cuevas

    Present address: Department of Psychology, European University of Madrid, School of Biomedical Sciences, Madrid, 28670, Spain

Affiliations

  1. Department of Neuroscience, The Scripps Research Institute, 10550 North Torrey Pines Road (SP30-2120), La Jolla, CA, 92037, USA

    • Gustavo Gonzalez-Cuevas
    • , Remi Martin-Fardon
    • , Tony M. Kerr
    • , David G. Stouffer
    • , Loren H. Parsons
    •  & Friedbert Weiss
  2. University of Maryland, School of Pharmacy, Baltimore, MD, 21201, USA

    • Dana C. Hammell
    •  & Audra L. Stinchcomb
  3. Zynerba Pharmaceuticals, Devon, PA, 19333, USA

    • Stan L. Banks

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The authors declare that they have no conflict of interest.

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Correspondence to Friedbert Weiss.

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https://doi.org/10.1038/s41386-018-0050-8